Managing GSH elevation and hypoxia to overcome resistance of cancer therapies using functionalized nanocarriers

Cancer is a fatal disease that is responsible for approximately 10 million deaths per year. This is due to complex mechanisms inside tumor microenvironment (TME) such as elevated GSH and hypoxia which reduce the curative effects of cancer therapies. The present review explores different approaches can target glutathione metabolic enzymes or their regulators to deplete GSH in cancer as well as overviewing role of natural compounds in disrupting GSH metabolism. Nanomedicine for many years was able to improve the efficacy and delivery of drugs using various forms of functionalized nanocarriers. Therefore, we summarize some of smart nanocarriers for chemotherapy, PDT, and SDT wither alone or combination used to reduce GSH level in TME with simultaneous rise of reactive oxygen species (ROS) levels. Furthermore, overcoming hypoxia and improving PDT could be accomplished by inhibiting hypoxia-induced factor – 1 (HIF-1), which is upregulated in TME, or using nanocarriers that deliver oxygen. Because SDT was able to replace PDT due to its deep penetration into tissues, its effectiveness was increased based on catalytic nanomedicine, which modulates TME via the efficient catalytic properties of nanoparticles. The current review offered future perspectives on the challenges, as well as potential solutions from various developed multifunctional nanoparticulate drug delivery systems to overcome elevated levels of GSH and hypoxia in TME.